HU176671B - Process for producing 1,6-bis-square bracket-5-bracket-4-chloro-phenyl-bracket closed-biguanido-square bracnet closed-hexane-disaccharinate - Google Patents

Description

The present invention relates to a novel process for the preparation of formula I

For the preparation of 1,6-bis [5- (4-chlorophenyl) -iguanido] -hexan-disaccharinate (hereinafter referred to as Idorhexidine disaccharinate), the base of the compound of the present invention and its known salts are widely used in medical practice under the name . well-established disinfectants. For example, they are suitable for disinfecting the surgical area, wounds, burned skin, surgical washings, as well as for preventing tooth decay and paradontosis. They are preferably used in pediatric, veterinary or cosmetic formulations, but are also used, for example, in disinfecting stables and animal husbandry devices.

Although chlorhexidine salts are generally of low toxicity (e.g. LD50 of 1800 mg / kg for chlorhexidine digluconate, 2000 ± 580 mg / kg for diacetate), they are generally of a very bitter taste and are therefore used for dental purposes / for disinfecting the oral cavity and throat. (eg pediatric dentistry, toothpastes, mouthwashes, etc.) is severely limited. Namely, the bitter taste induced by the chlorhexidine salts in the formulations can only be attenuated by the addition of various syrups and maturing sweeteners or 0.1-1.5% lactic acid (see, for example, U.S. Patent Nos. 3,925,543, 3,989,813 and 4,025,616). Dutch Patent Publication No. 7,606,824; Belgian Patent No. 837,579; French Patent Publication Nos. 004278 and 006222; and Japanese Patent Publication No. 01 2570). However, this has many disadvantages.

such as the possible incompatibility of the additive used (see, for example, French Patent Publication 004278) or the possible reduction of its effect; specifically contraindicated precisely because of the presence of fermentative products that promote the formation of dental caries) and finally the fact that chlorhexidine digluconate and chlorhexidine diacetate commonly used in dental caries prevent severe discolouration of the teeth.

Surprisingly, it has been found that all these drawbacks can be overcome by using the new chlorhexidine disaccharinate of the present invention instead of the known chlorhexidine salts. The novel chlorhexidine salt of the present invention has the following advantages:

a) The taste is not bitter, but pleasantly sweet.

(b) Minimum toxicity (measured in mouse)

LD _So > 5000 mg / kg po (no mortality observed during 1 week observation period).

c) The compound is stable.

d) Its water solubility is very low (0.0015 g of chlorhexidine disaccharate is soluble in 100 ml of water), which is very favorable for the stability and compatibility of the compound in the formulations.

e) Otherwise, its very low water solubility is just enough to achieve the maximum effect, and consequently the activity of the disaccharide converted to base is the same as that of the other chlorhexidine salts.

(f) It does not contain a fermentable component and is therefore well suited for use in compositions for the prevention of dental caries which do not require the addition of any specific stabilizing agents.

g) Does not discolour the teeth.

h) According to our tests it does not cause irritation of the mucous membrane (irritation).

i) When used in suspension, it adheres well to the teeth, which, due to their low water solubility, remain stable for a long time.

Chlorhexidine disaccharinate according to the invention is prepared by the addition of 1 mol of chlorhexidine base and

A mixture of saccharin (2-2.6 mol, preferably 2-2.05 mol) is warmly dissolved in an organic polar solvent and then allowed to crystallize. After cooling, the product crystallizes in a clear, uniform manner. The product is swallowed from the reaction mixture by simple filtration. The polar organic solvents used are lower alcohols or ketones, preferably methanol, ethanol or acetone, dimethylformamide, dimethylsulfoxide or acetonitrile. The disaccharate thus obtained is pure and can be used directly for the preparation of both pharmaceutical and cosmetic preparations. Due to its favorable taste, solubility and toxicity data it is particularly suitable for the preparation of various dental, oral and throat disinfectants. A special advantage is that the teeth do not discolour during application.

The following examples illustrate the preparation of the novel compound of the present invention and some of its uses:

Example 1

A mixture of 20.2 g (0.04 mol) of chlorhexidine base and 14.65 g (0.08 mol) of saccharin is dissolved in 250 ml of boiling methanol with stirring. The solution was filtered and allowed to crystallize. On cooling, 31.7 g (90.9%) of the solution precipitated pure chlorhexidine disaccharate, m.p. 224-226 ° C. The mother liquor is ca.

Evaporation to 50 ml gave an additional 3.0 g (8.6%) of product, mp 223-226 ° C. Analysis: C ₃₆ H ₄ O ₁ Cl ₂ Ni ₂ O ₆ S ₂ (871.82 molecular weight) per formula Calculated: C, 49.59; H = 4.62%, N = 19.28% S = 7.36% Cl = 8.13% Found: C, 49.38%, H = 4.99% N = 19.05% S, 7.53% Cl = 8.01%.

Biological value measurement:

Method: Agar Diffusion Method (F. Kavanagh: Analytical Microbiology, Vol. II, Academic Press, New York, 1972, p. 323)

Indicator: Bacillus subtilis ATCC 6633

Standard: Chlorhexidine gluconate B.P.

The two compounds have the same activity converted to bases. (From a solution of 250, 125, 62.5 / zg / ml in methanol, determined in a volume of 0,1 ml.)

Experimental error: max. ± 2%.

Example 2

All were carried out as in Example 1, except that 18.31 g (0.1 mol) of saccharin were used.

Yield: 32.0 g (91.7%) of chlorhexidine disaccharinate, m.p. 224-226.

The product is the same as that obtained in Example 1. The mother liquor is ca. Reduced to 50tnl more

2.5 g (7.1%) of product are obtained, m.p. 222-225 °

Example 3

In each case, the procedure of Example 1 was followed except that 250 ml of acetone was used as solvent.

Yield: 32.1 g (92.1%) of chlorhexidine disaccharate, m.p. 224-226 °.

The product is the same as that obtained in Example 1. The mother liquor is ca. Reduced to 40ml more

2.2 g (6.3%) of product are obtained, m.p. 223-226 °.

Example 4

In each case, the procedure of Example 1 was followed except that 150 ml of dimethylformamide was used as solvent.

Yield: 30.1 g (86.3%) of chlorhexidine disaccharate, m.p. 224-226 °. .

The product is the same as that obtained in Example 1. Add 100 ml of water to the mother liquor to give an additional 3.8 g (10.9%) of product, mp 223-226 °.

Example 5

Throat disinfectant tablet composition:

Chlorhexidine disaccharinate 5 mg norcaine (HI. Hg. VI.) 2 mg sucrose 762 mg corn starch 160 mg solid paraffin 1 S mg talc 30 mg magnesium stearate 20 mg mint aroma 6 mg

Each tablet weighs 1000 mg

Technology: according to the general rules for making tacuettes.

Example 6

Production of a dental brush for the prevention of tooth decay (caries prophylaxis) for the treatment of periodontal disease and chronic gingivitis (chronic gingivitis).

Ingredients:

Chlorhexidine disaccharinate 2 g

Huronic F 68 ^R (Degussa) 0.9 g (polyoxyethylene-polyoxypropylene block polymer) gives 100 g of distilled water

Technology; Chlorhexidine disaccharinate is suspended in an aqueous solution of the block polymer according to the general rules for suspension preparation. The product does not cement and can be homogenized by gentle agitation.

Example 7 25

Toothpaste Preparation Composition: 30

Chlorhexidine disaccharinate 2g kalciumfoszfáthidrát 20g precipitated calcium carbonate 17g glycerol 15g Sodium lauryl sulfate 12g colloidal silicon dioxide 2g perfume and aromatic substances 2g distilled water ad 100 g Technology: toothpaste making according to the rules. general

Example 8 Preparation of toothpaste gel (transparent) Ingredients: Chlorhexidine diszacharinát 2g Carbopol 940 ^R (Goodrich Chem. Corp.) 1.2 g (Carboxyvinyl) sodium hydroxide 0.5 g Sodium lauryl sulfate 15g glycerol 20g 96% ethyl alcohol 20g Tween-20 2g flavorings 5g distilled water adlOOg

Technology: according to the general rules of toothpaste-gel preparation.

Example 9

Preparation of aerosol toothpaste preparation: 5

Chlorhexidine disaccharinate 2 g

Carbopol 940 ^R (Goodrich Chem. Corp.) 1.2 g (carboxyvinyl polymer) sodium hydroxide 0.5 g sodium lauryl sulfate 5 g calcium phosphate dihydrate 32 g glycerol 30 g

96% Ethyl Alcohol 5g Flavorings Add 5g distilled water to 100g

Propellant: nitrogen gas

Technology: General rules for toothpaste and aerosol preparation.

Download: in metering valve bottles.

Example 10

Preparation of toothpaste preparation: Composition:

Chlorhexidine disaccharinate 2 g of precipitated calcium carbonate 78 g of magnesium carbonate 10 g of sodium lauryl sulphate 5 g of flavoring and coloring agents 5 g

Technology: according to the general rules of tooth-making.

Example 11

Preparation of mouthwash:

Ingredients:

Chlorhexidine disaccharinate 2 g

Huronic F 68 ^R (Degussa) 0.9 g (polyoxyethylene-polyoxypropylene block polymer) flavoring 7.5 g

70% ethyl alcohol gives 100 g

Technology; according to the general rules of mouthwash preparation.

Example 12

Preparation of aerosol mouth freshener with disinfectant composition:

Chlorhexidine disaccharinate 2 g

Huronic F 68 ^R (Degussa) 0.6 g (polyoxyethylene-polyoxypropylene block polymer) flavorings 1.5 g

96% ethyl alcohol gives 40 g of distilled water per 100 g

Hair Gas: Nitrogen

Technology: according to the general rules of solution and aerosol preparation.

Download: in metering valve bottles.

Claims (5)

A process for the preparation of a novel 1,6-bis [5- (4-chlorophenyl) biguanido] hexane disaccharinate (chlorhexidine disaccharinate) of formula I, characterized in that chlorhexidine base and saccharin are 1: 2-2. A 6 molar mixture of 10 was dissolved in an organic polar solvent while hot, and after cooling, the crystallized product was filtered off. 2. A process according to claim 1 wherein the polar organic solvent used in the salt formation is methanol, acetone or dimethylformamide. 3. A process for the preparation of a pharmaceutical composition according to claim 1, wherein the chlorhexidine disaccharinate together with the pharmaceutical excipients is converted into a medicament. 4. The process of claim 1 for the preparation of a cosmetic composition, in particular an oral throat disinfectant, characterized in that the chlorhexidine disaccharinate, together with the pharmaceutical excipients, is converted into a tablet or dental brush composition. 5. The further development of the method according to claim 1 for the preparation of cosmetic compositions, in particular mouthwashes, toothpastes, toothpaste gels, aerosol toothpastes, toothpastes or disinfectant aerosol mouth freshening compositions, characterized in that chlorhexidine disacchar gel, aerosol toothpaste, toothpaste or disinfectant mouth freshener. Figure 1 Responsible for publishing: Director of Economic and Legal Publishing 814183 - Zrínyi Printing House, Budapest * International Classification: C 07 D 275/06, 129/16 I